Autism Studies 2012;1:1

Do infectious fever and fluid/salt diets relieve 
autistic behavior by elevating brain glutamine 
and accelerating cortical metabolism? 

ABSTRACT

Parents and pediatricians have long known autistic behavior often remits during infectious fever, often dramatically, yet how this happens is far from clear. Hot baths rarely relieve autistic behavior similarly, probably because fever raises brain temperature much more than ambient heat (especially in children). Fever is a complex metabolic and immune response, yet a much simpler event that relieves autistic behavior noticeably has recently been reported – fluid/salt diet a day or two before medical procedures (e.g. colonoscopy). One unifying explanation derives from evidence that the ratio of sodium ions to calcium ions in the hypothalamus determines the set point for body temperature; when fever raises the set point, sodium ions enter cells and calcium ions leave. Salt solutions also raise the set point (albeit much less) by exchanging blood sodium for brain calcium. Sodium generates fuels by taking up glutamate into astrocytes for neutralization to glutamine, and activating the sodium pump, indirectly converting glucose to lactate. Because children with high brain glutamine from urea cycle disorders rarely show autistic behavior, the simplest explanation for relief by fever and fluid/salt diets may be that fasting releases glutamine from skeletal muscles as provisional fuel. Observers implicated insufficient brain energy and delayed cortical maturation in autistic disorders. Is autistic behavior ‘released’ by lack of energy in the inhibitory cerebral cortex?

INTRODUCTION

October 15th, 2011, emails were sent to 235 U.S. practitioners listed on the Autism Research Institute (ARI) website [1], inquiring about salt cravings and low blood sodium in children with autistic disorders (ASD). Attached was a paper recently published by Medical Hypotheses: “Do salt cravings in children with autistic disorders reveal low blood sodium depleting brain taurine and glutamine?”[2] Two weeks later a similar email+pdf was sent to 100 international practitioners listed on the ARI site. Of 60 practitioners who replied, the great majority reported plasma or serum sodium was normal in their ASD patients, even in those who craved salt. Six practitioners, however, replied hyponatremia was not uncommon in their patients. In some ASD children salt cravings signified adrenal insufficiency; in others, magnesium, iodine, or zinc deficiencies. 

But if blood sodium concentrations are usually normal in these children, why do fluid/salt diets a day or two before invasive medical procedures (e.g. colonoscopy) relieve autistic behavior noticeably [3]? Is this an example of fear of medical procedures (e.g. blood drawing) provoking sudden remissions [4,5]? Another explanation might be increased blood pressure from salt [6]. This could help ASD children with adrenal insufficiency and low blood pressure – but many have accelerated hearts and high blood pressure, apparently from stress [7,8]. 

A better explanation for the benefit of fluid/salt diets may be an explanation for the benefit of infectious fever, which often relieves autistic behavior (often dramatically) for the duration of the fever [4,9-11]. Myers and Veale proposed the set point for body temperature is determined by the ratio of sodium ions (Na+) to calcium ions (Ca2+) in the hypothalamus; when fever raises the set point, sodium ions enter cells and calcium ions leave [12]. In light of recent evidence suggesting calcium accumulation in autistic brains [13], do fever and fluid/salt diets relieve autistic behavior because extracellular sodium displaces intra-cellular calcium? Or do they help because sodium raises the set point, accelerates brain metabolism, and generates metabolic fuels? 

INFECTIOUS FEVER RELIEVES AUTISTIC BEHAVIOR 

Though there is practically no mention of the high fever/improved behavior phenomenon in the entire autism literature, every knowledgeable person – both parent and professional – I approached for information knew of it. Sullivan 1980 [4] 

Anecdotal reports of fever’s benefit were published by Sullivan in her column Parents Speak in the Journal of Autism and Developmental Disorders. Campbell described an outbreak of upper respiratory infection in a Bellevue Hospital nursery. Autistic children with fevers of 102°–105° had longer attention spans and socialized with other children and adults. Most improvements subsided a few days after temperatures returned to normal. Caparulo and Cohen noted stressful medical procedures like blood drawing also provoked brief dramatic remissions. Sullivan: “[T]he change in the autistic child’s behavior [from fever] is more than quiet – it is a lucid calmness, as though he suddenly has a better understanding of what is happening around him.”[4]
 
Cotterill reported the phenomenon in 1985: “When autistics have a moderate fever, they invariably display dramatically more normal behav-ioural patterns, including a greater desire or ability to communicate.... The effect appears to reach a maximum for fevers in the range 1.5°–2.5°C [2.7°– 4.5°F].” [9] Brown described his personal observations in 1999 [10] and 2004: “[T]he changes that occur in these autistic children are ... dramatic, more like a metamorphosis in which the autistic child suddenly becomes almost normal. These children experience increased alertness, a decrease in social isolation and self-injurious behavior, an increase in verbal behavior, and an attempt to reach out and communicate with adults. And they don’t appear to be that sick.”[11] 

These anecdotal reports inspired a prospective study by Curran et al., who compared the behavior of 30 ASD children during fevers greater than 100.4°F (38°C) against the behavior of 30 ASD children with no fever. More than half the parents already knew fever helped. During fever most parents observed less irritability, hyperactivity, repetitive acts, and inappropriate speech, which appeared to not depend on the severity of the illness, height of the fever, nor degree of lethargy [14]. Publication of this study provoked a spontaneous outpouring of parents’ reports of relief by fever in autism, ADHD, and other disorders. Surprisingly, three autistic children improved briefly from a sauna, steam room, or hot tub/bath. Zimmerman et al. concluded: “These reports suggest that methods for raising the core temperature may be as effective as fever in some individuals, and their rapid onset and transient nature might involve separate pathways from fever and immune responses.”[15] Informal parent surveys indicate fever helps 30–40% of ASD children [16]. 

Mehler and Purpura proposed fever relieves autistic behavior by transiently normalizing the activities of the locus coeruleus (ceruleus) in the brainstem and its network of sympathetic nerves – the brain’s primary source of norepinephrine. These writers proposed the locus coeruleus and its sympathetic network become dysregulated during development, impairing their functions in thermoregulation and behavior. They noted relief of autistic behavior by fever argues “neural networks responsible for ASD, particularly in higher functioning patients, should be functionally intact.”[17] 

A workshop on fever in autism [16] considered the effect of temperature to increase brain blood flow (consistently low in these children), but the usual lack of benefit of a hot tub or sauna argued against it [18]. The best explanation may be Kiyatkin’s observation that fever elevates human brain temperature much more than ambient heat, especially in children: “In contrast [to fever], sauna or environmental warming affects brain temperature very little, especially in humans, because of sophisticated homeostatic mechanisms that maintain stability of body temper-ature.”[19] 

How does fever elevate brain temperature? 

Febrile illness is a natural stressor and a powerful stimulus of both the adrenal medulla and cortex. Keil et al. 2010 [20] 

Because neurons require several orders of magnitude more metabolic energy than other cells (largely to restore resting potentials) the brain generates considerable heat [21]. Heat accelerates metabolic rate about 11% for each °C [22], so the hypothalamus regulates body and brain temperatures closely, normally 98.0°–98.8°F (36.6°–37.1°C) orally [23]. Temperature-regulating centers in the hypothalamus resemble thermo-stats in a home heating/cooling system. Hypothalamic ‘thermostats’ regulate and integrate the independent heating and cooling mechanisms of the body to stabilize temperature at the most appropriate set point. When bacterial or viral infection triggers the hypothalamus to raise body temperature to a new set point called fever, cooling mechanisms of vasodilation and sweating are suppressed as temperature rises. When fever plateaus at the new set point, skin blood flow returns to balance heat gain and loss, and the child feels neither cold nor hot [24]. When fever breaks (crisis or flush), skin blood vessels dilate abruptly and sweating is profuse [23]. 

Fever resembles the body’s response to cold – skin vessels constrict to conserve heat, and heat is generated by muscle contractions (shivering) and acceleration of metabolism [25]. Metabolic (nonshivering) thermo-genesis during cold is stimulated by the sympathetic nervous system (SNS) transmitter norepinephrine [26]. Thermogenesis by fever may be largely stimulated by epinephrine from the adrenal medulla, which accelerates metabolism 5–10x more than norepinephrine [23]. 

Current views of fever implicate environmental pyrogens (fever-inducing agents) like bacteria triggering internal pyrogens (interleukins, prosta-glandins) that directly stimulate heat production. Tang and Kiyatkin: “It is unclear, however, whether this effect is triggered centrally (i.e., via brain metabolic activation and subsequent involvement of sympathetic mechanisms) or results from the direct action of endogenous pyrogens on peripheral heat-producing organs (i.e., liver, muscle, adipose tissue).... In addition, these substances affect multiple afferent pathways to the brain, thus transmitting a signal from the periphery and inducing metabolic brain activation.”[27] Roth argued the heat of fever arises in the periphery, then is carried by blood to the body core and brain: “The prostaglandins released in the periphery have no direct effect on heat production, but are transported into the brain and contribute to the shift of the set-point.”[28] 

What is not disputed is that during fever the SNS accelerates metabolism. Sympathetic thermogenesis is most obvious in stimulation of newborn brown fat by norepinephrine, and mobilization of metabolic fuels (fatty acids, glucose from glycogen) by epinephrine. These catecholamines also accelerate metabolism during stress, generating an elevated temperature called stress fever. Stress fever is genuine fever – body temperature reset to a higher set point, stimulating heat conservation and production [29]. Kiyatkin concluded stress fever “may best be viewed as a consequence of a more general phenomenon of ‘arousal-related’ brain hyperther-mia.”[21] Why doesn’t stress fever relieve autistic behavior? Kiyatkin: “While data in humans are limited, it appears that fluctuations due to stress, environmental warming, etc. are relatively weak (up to 1.0°–1.5°C), but during fever this increase is much larger, especially in children.”[19] 

Although plasma catecholamines cannot cross an intact blood-brain barrier, some sympathetic neurons in the brainstem synthesize epin-ephrine [30]. Wortsman was convinced adrenal epinephrine during acute stress reaches the brain: “The plethora of central effects indicates access of the catecholamine to the CNS. This would be possible only in areas devoid of blood-brain barrier. There are two hypothalamic structures with these properties; one is the median eminence, and the other is the organum vaculosum laminae terminalis.... The hypothalamus itself is a rich source for epinephrine, having the highest concentrations in the brain in most species.”[31] 

HYPOTHESIS

Do fever and fluid/salt diets relieve autistic behavior by releasing glutamine from skeletal muscles, accelerating brain metabolism? Is autistic behavior ‘released’ by insufficient energy in the inhibitory cerebral cortex? 

If fever relieves autistic behavior by accelerating brain metabolism, how might salt do the same? One clue comes from Frosini, who studied the effects of ambient heat vs. fever to release amino acids and the cations sodium (Na+), potassium (K+), calcium (Ca2+), and magnesium (Mg2+) from rabbit brain into cerebrospinal fluid (CSF) [32]. Heat increased CSF calcium, but fever increased it much more; only fever decreased CSF sodium. Frosini cited Myers and Veale’s proposal that fever raises the set point by moving sodium ions into the posterior hypothalamus that displace calcium ions [12]. Stanton et al. found the cytokine interleukin, key mediator of the fever response, increased intracellular Na+ and decreased intracellular Ca2+ in immune cells of mice [33]. 

Sodium ions moving from blood or CSF into astrocytes trigger the sodium pump (Na+/K+-ATPase) to remove them. The sodium pump is an adenosine triphosphatase (ATPase) – intrinsic membrane enzyme protein that transports ions across cell membranes against their concentration or electrochemical gradients using energy derived from ATP. Na+/K+-ATPase exports three intracellular Na+ ions and imports two extracellular K+ ions. This maintains and restores the steep Na+ and K+ gradients across membranes that polarize neurons and initiate and conduct nerve impulses. These ion gradients also provide energy for secondary transport processes including sodium/calcium exchange, uptake of nutrients and neurotransmitters against their concentration gradients, and shifts of molecules to regulate cell volume and pH [34]. 

The sodium pump keeps intracellular sodium concentrations very low and extracellular concentrations very high. This sodium gradient is stored (potential) energy that is slowly and continually released as sodium ions leak through plasma membranes into cells from the pressure of their high external concentration and positive charge, and are transported into cells via membrane carrier proteins. Sodium cotransport uses a carrier protein that binds both substances outside the membrane. Sodium countertransport uses a carrier protein that binds sodium outside the membrane and another substance inside [23]. The sodium pump requires glucose as fuel, which astrocytes convert to lactate, a fuel neurons prefer [35]. Extracellular sodium also carries the excitatory transmitter glutamate released at synapses into astrocytes, which detoxify glutamate and ammonia by combining them to form glutamine [36]. 

Impairments of the sodium pump described by Benarroch [34] greatly resemble pathologies detected or suspected in autistic disorders. First, loss of sodium gradients reduces uptake of glutamate by astrocytes. Wakefield et al. suspected glutamine was low in autistic brains because glutamate transporters were impaired [37]. Blaylock implicated extra-cellular glutamate accumulation in autistic hyperactivity [38]. 

Second, impairment of the sodium pump requires that the sodium/calcium exchanger remove sodium, accumulating intracellular calcium. Calcium accumulation impairs ATPase pumps by competing with magnesium ions required to hydrolyze ATP. Evidence suggesting calcium accumulation in autistic brains has been reported [13]. Magnesium/vitamin B6 supplements have been most effective in children and adults with ASD [39]. 

Third, ion gradients maintain cell volume. Astrocytes appear swollen in ASD [40], the osmolyte myoinositol is elevated [41], and osmolytes taurine and glutamine appear depleted [37,42]. Benarroch: “The inability to maintain transmembrane Na+ and K+ gradients results in collapse of the membrane potential; impaired activity of glutamate transporters; secondary Cl– [chloride] and water influx and thus intracellular swelling; and accumulation of intracellular Ca2+.”[34] 

But if the sodium pump is impaired in these children, why was it high in their brains? Ji et al. assessed the brains of ASD children postmortem for activity of the sodium pump and calcium pump (Ca2+/Mg2+-ATPase). They detected normal concentrations of these enzymes in the occipital, parietal, and temporal lobes, but elevated concentrations in the cerebellum and frontal lobes. Citing other evidence of abnormal calcium metabolism in ASD, they concluded: “Increased activity of these enzymes in the frontal cortex and cerebellum may be ... compensatory responses to increased intracellular calcium concentration in autism.”[13] 

Might these enzyme proteins be high to compensate impairment of their function? The sodium pump is also activated by sodium influx into excitable cells under stress [43]. Epinephrine during fever activates the skeletal muscle sodium pump. Bundgaard et al. injected healthy humans with endotoxin and detected increases in plasma epinephrine (but not norepinephrine), lactate, and activity of Na+/K+-ATPase [44]. They concluded the skeletal muscle sodium pump is stimulated by beta2-adrenergic receptors of the SNS – activated virtually exclusively by epinephrine. 

But if stress (like salt and fever) moves sodium into the brain, why does stress usually aggravate autistic behavior [8]? One intriguing explanation is that stress catecholamines inhibit the prefrontal cortex – ‘releasing’ behavior [45]. But fever too elevates catecholamines (notably epineph-rine) – so why does stress aggravate and fever relieve? For one, norepinephrine and dopamine suppress the prefrontal cortex more than epinephrine [45]. Fever also accelerates brain metabolism much more than stress, especially in children [19]. Finally, the loss of appetite (anorexia) of fever releases glutamine from skeletal muscles into blood as provisional fuel [46,47]; stress decreases plasma glutamine, apparently because cells require more glutamine than muscles release [48]. 

Is there enough sodium in a fluid/salt diet to generate glutamine and lactate that accelerate brain metabolism significantly? Far less sodium exchanging for calcium may be needed to raise the set point. Myers and Veale: “It would seem that only a slight and very transient reduction of Ca2+ in the blood which bathes the posterior hypothalamus would be sufficient to shift the balance between the Na+ and Ca2+ ions, after which the set point is raised. During the period of Ca2+ deficiency, hyperthermia would occur. Our experiments seem to mimic this condition, since even a short-term imbalance between Na+ and Ca2+ caused a pyrexic response. Moreover, it has been reported clinically that a hypernatremia can be associated with an intense prolonged febrile response.”[12] 

Nielsen studied temperature regulation in healthy humans who drank a liter of hypertonic sodium chloride (NaCl) or calcium chloride (CaCl2) solution before bicycling. Temperature plateaued at a higher level after the saline solution [49]. Harrison et al. studied dehydration hyperthermia in healthy males ingesting water or saline solution before bicycling: “Deep body temperature was consistently higher with saline replacement than with water replacement.”[50]
 
Thus sodium entering the brain from CSF (fever) or blood (fluid/salt diet) raises the set point, displaces calcium, carries glutamate into astrocytes for neutralization to glutamine (detoxifying glutamate and ammonia), and activates the sodium pump, indirectly converting glucose to lactate. Even so, in light of the notable lack of autistic behavior in children with high brain glutamine from urea cycle disorders (UCD), the simplest explanation for the benefit of fever and fluid/salt diets may be that fasting releases glutamine from skeletal muscles as provisional fuel. If fever increases cerebral cortical functions like awareness, speech, communication, and self-control, is autistic behavior essentially ‘sub-cortical’? 

SALT/WATER METABOLISM IN AUTISTIC DISORDERS

Sixty U.S. and international ARI practitioners replied to an inquiry about salt cravings and low blood sodium (hyponatremia) in children with autistic disorders, based on evidence of high arginine vasopressin (AVP), salt cravings, relief of behavior by fluid/salt diets, and depletion of brain osmolytes taurine and glutamine [2]. The great majority replied plasma or serum sodium was normal in their ASD patients, even in those who craved salt. Most revealing replies: 

“We saw over 6,000 ASD patients; it was very rare to ever see a low sodium.” 
“I have not seen any evidence of low blood sodium in my autistic patients. It is generally in the normal range. Most do not crave salt unless they have adrenal problems, which is rare.” 
“I have wondered about kids with salt craving. I worried about hypo-natremia secondary to SIADH [inappropriate secretion of antidiuretic hormone vasopressin]. They have had normal sodium levels. I have also worried about kids with extensive thirst. They also had normal sodium levels.” 
“We do a lot of blood work and see very few kids with hyponatremia. We do see a lot with salt cravings and often this is due to iodine deficiency or magnesium deficiency.” 
“I have not seen hyponatremia in any patient I’ve tested (out of hundreds). I have seen some who do crave salt, though.” 
“I have not generally seen low sodium in my practice. I have only about 2 or 3 patients who seem to crave salty foods and their serum sodium is always within the normal range.” 
“I have not [seen hyponatremia], and have checked more than 1000 kids for sodium/potassium/chloride. I actually see increased whole blood sodium and decreased whole blood potassium most.” 
“We do talk about food cravings and salt does not usually come up.” 
“I have checked kidney profiles on over 2000 children with autism and I rarely, if ever, see hyponatremia.... I have occasionally seen salt cravings (less than 1% of patients) and in those I have checked sodium urine and blood levels and have not seen abnormalities.” 
“I have yet to see a child with ASD demonstrate symptoms of hypo-natremia. I know there are a few studies which refer to hyponatremia in this ... population, however they are all very old studies.” 
“It isn't something I have noticed as far as true clinical hyponatremia. I may have seen some on the lower end of the reference ranges – but nothing in particular stands out. I generally think about adrenal dysfunction in these cases.... I have definitely seen concentrated urine – but a lot of these kids have difficulty consuming enough water (don’t like the taste).” 

Only six of sixty practitioners reported detecting hyponatremia in their ASD patients, but some found it common: 

“Hyponatremia is not uncommon in my autism patients who have electrolyte loss secondary to diarrhea from gastrointestinal disturbances.” 
“Yes, many times I do find that a low blood sodium is common with my patients with ASD.” 
“I saw hyponatremia down to 129 mmol/L in some not all.” 
“I have noticed that trend over the years.” 
“Of the non-supplemented kids I have tested for salt (along with other metals) [in urine]: 
1 extremely high salt (do not know about dietary sources) 
1 normal 
3 low normal 
2 well below normal” 
“I believe the low blood sodium is a result of chronic adrenal stress syndrome. My experience has been that the child will even be compelled to lick their lips and/or arms/body parts to reclaim the salt because of their stress and subsequent low sodium levels.” 

Two conclusions are clear from these replies. Salt cravings are fairly common in ASD; hyponatremia is unusual – or unnoticed. One explanation is that blood sodium is a measure of water more than sodium. Vincent: “Serum sodium is a concentration of sodium, and actually tells you more about the water level in the body than it does the sodium level. It is more related to the function of antidiuretic hormone (vasopressin) than anything to do with actual sodium management.... If you want to decide whether an individual is truly low in sodium, a better value to use is something called the fractional excretion of sodium. It tells you how avidly the body is ‘hanging on’ to sodium, by showing what percentage of the person’s sodium is being dumped into the urine. If someone is significantly salt-deficient, they will be losing less than 1% into the urine.”[51] Another practitioner pointed out that because blood sodium is so closely regulated, absence of hyponatremia does not rule out sodium deficiency or spilling in urine. 

A pediatric nephrologist explained this and other aspects of salt/water metabolism in ASD lucidly: “You can have salt wasting with increased salt appetite with a normal [blood] sodium. It is usually during a stress response when the sodium drops.... If you argued that ASD patients have a blunted [stress] response and crave salt in response to stress, I could not argue with that and you would most likely not see hyponatremia nor would hyponatremia be a requirement for the salt craving. The body would immediately sense the salt depletion [before] a clinically significant fall in serum sodium and the salt appetite would start.... Increased salt appetite is a physiologic response to salt depletion, but increased salt appetite does not increase blood sodium. The Japanese have extremely high sodium diets due to soy sauce but have a normal serum sodium.... It could be that patients with ASD are intermittent salt wasters and this may or may not be due to subclinical adrenal dysfunction. This is far more plausible than elevated AVP or sex steroids. Elevated AVP is a secondary response to salt wasting; secondary salt wasting from a primary disorder in AVP does not result in salt craving but in water intoxication.”[52] 

Arginine vasopressin (AVP) also rises during stress. The adrenal cortex responds to stress by releasing cortisol and aldosterone. Aldosterone retains sodium and water at the kidneys to maintain blood volume and pressure. When aldosterone is depleted or the adrenocortical stress response is impaired, blood volume is maintained by vasopressin released by the pituitary, which conserves water at the kidneys. High vasopressin has been detected in ASD children [53], and suspected for various reasons [54,55], notably high androgens [56,57], and the frequency of gastroenteritis, hypoglycemia, and stress, which release vasopressin. Vasopressin is also a powerful cerebral vasoconstrictor [58] that might explain low brain blood flow in ASD. Leshem noted overproduction of adrenal testosterone reduces substrate for aldos-terone, inducing salt wasting and salt appetite [59]. 


Other observations by ARI practitioners: 
“I do see salt cravings in ASD children, but not as significant as gut issues and sugar cravings.... I think salt craving always indicates some kind of human mineral deficiency – sodium, magnesium, potassium, zinc, etc. It’s just that sodium and potassium deficiencies lead to more acute symptoms.” 
“Salt cravings are often associated with adrenal fatigue and I see an unusual amount of exhausted adrenals in these kids (as per their epinephrine/norepinephrine residues in organic acid testing and below normal Na/K in hair mineral analysis).” 

Salt cravings are common in herbivores because plants are low in sodium. Whether man has retained a similar salt urge is controversial. Morgan concluded: “[W]hen an animal has had enough salt it will take no more. In humans neither the compulsory search nor the abrupt cut-off point can be relied on. Their intake bears no relation to salt deficit or surplus.”[60] On the other hand, Leshem contended: “I argue that humans do not have a sodium appetite as we know it in animals, leaving us with a rather limited understanding of why humans ingest so much salt.... One heretical possibility – emanating from the intense drive for salt we have, our resistance to reducing its intake, and the argument of the ‘wisdom of the body’ as we know it from animals – is that human excess salt intake is not such at all. While it certainly exceeds the requirements of a static model of physiological sodium balance as we know it ... it may be that our bodies require a higher sodium turnover.... [S]urreptitious reduction of dietary sodium over days or weeks induces a partial compensatory response ... but note that even this partial compensatory behavior maintains sodium intake well above the conven-tionally accepted sodium requirement. Using the adaptive rationale, might we assume that there is some utility to this obdurate defense of excess? Could it somehow be related to the processing or absorption of the enormous and varied amounts of food we ingest, to the stress, well-being, or mental functioning in lifestyles attendant on high sodium societies?”[59] 

Eating salted soup (1 tsp/6g NaCl/400ml) elevated plasma sodium and blood pressure rapidly and for hours [6]. Friedman found elevating extracellular sodium shifted sodium into vascular smooth muscle, caus-ing contraction and increased blood pressure [61]. de Wardener et al. concluded eating salt elevates plasma sodium slightly, which draws water out of cells to balance osmolarity, increasing blood volume and pressure [62]. That should help ASD children with low blood pressure from adrenal fatigue – but what about those with high blood pressure? 

Stress catecholamines, accelerated hearts, 
high blood pressure, exhausted adrenals 

It is not my experience that [ASD children] usually have high blood pressure [BP] and heart rate. When epinephrine/norepinephrine are being pumped out under stress, it would initially have an effect on BP but as time goes by, the adrenals become exhausted and then we usually have the opposite effect, which is low everything, BP and catecholamines in urine. Dumas 2011 [63] 

The ‘lucid calm’ fever induces in autistic children appears qualitatively different from the lethargy of fever, according to anecdotal reports and Curran et al. [14]. Lucid calm without fever is well-captured by the photography of Balsamo; there is no fear in these “autism eyes.”[64] Yet these dilated pupils [65], along with accelerated hearts at rest [8], and high blood pressure [7] reveal an ongoing stress response in these children, fueled by the adrenal hormone epinephrine and the sympathetic transmitter norepinephrine. 

Under stress and sympathetic stimulation the medulla of the adrenal gland secretes about 80% epinephrine and 20% norepinephrine [23]. Most norepinephrine is a transmitter along SNS pathways arising in the brainstem [66], and along right-hemisphere sensory pathways [67]. Catecholamines redistribute blood: norepinephrine constricts arteries and arterioles; epinephrine constricts them less or dilates them. Epinephrine increases heart rate and force of contractions more than norepinephrine, elevates blood pressure less than norepinephrine [23]. Epinephrine appears to be the major regulator of short-term blood glucose levels, blood glucose in newborns, and the primary responder to acute hypogly-cemia in older children [20]. Stress-induced and exercise-induced epinephrine increase brain metabolism and blood flow [68,69]. 

Adrenal epinephrine is mobilized by global threats like shock, emotional distress, and hypoglycemia; norepinephrine is mobilized for active attack or avoidance (fight-or-flight) [70]. Norepinephrine is associated with anger and aggression; epinephrine is associated with fear, anxiety, tension, and passive immobility (frozen fear) [70-72]. Autistic children are often anxious and fearful [8], also vigilant and overfocused [73] – other effects of epinephrine [74]. Catecholamine measurements tend to corroborate signs of sympathetic hyperactivity. Trottier et al. noted that various independent studies found epinephrine and norepinephrine elevated in plasma [75]. Young et al., however, detected significantly less norepinephrine and epinephrine in urine of severely impaired autistic boys [76]. Launay et al. found epinephrine and norepinephrine elevated in plasma, normal in urine, and low in platelets; dopamine was normal in urine and low in platelets [77]. Because platelets are reservoirs for catecholamines and other molecules [78], low levels may reveal depleted reserves. 

Ming et al. investigated baseline autonomic function in autistic children with or without autonomic symptoms. Cardiac vagal tone (indicating parasympathetic activity) was lower, and heart rate, mean arterial pressure, and diastolic pressure higher in all the autistic children, whether or not they showed autonomic symptoms [7]. Cohen and Johnson found autistic children at rest had accelerated hearts and increased forearm blood flow (signs of epinephrine), but whether this was a primary dysregulation or a reaction to the strange environment was unclear. They concluded autistic children may defensively withdraw from “overwhelming environmental bombardment.”[79] 

Jansen et al. found the stress of public speaking increased salivary cortisol in autistic children, yet their heart rates did not accelerate proportionately. Heart rates during bicycling did not differ from controls [80]. A follow-up study of autistic adults revealed a small norepinephrine response to public speaking, and a smaller epinephrine response. Epin-ephrine may have even fallen, to judge from their graph. They suggested “chronic anxiety and resulting state of hyperarousal has resulted in a downregulation of the autonomic nervous system and a reduced responsivity to stress.”[81] 

Goodwin et al. studied stress responses in five low-functioning autists 8–18 years old. Baseline heart rates (HR) averaged 20 beats per minute faster than controls, yet accelerated in response to stress one-third as often: “[P]ersons with autism who have high basal HR are unable to elicit significantly greater increases in cardiovascular reactivity to environ-mental stimulation.... It may well be that some individuals with autism look relatively calm overtly, but are experiencing significant physiological arousal covertly.... [S]tressful events frequently precipitate the maladap-tive behavior problems seen in this population, such as aggression, self-injury, tantrums, and destruction of property.” Autistic children are more anxious and fearful than typical children, they concluded – especially afraid of noises, other people, and the dark [8]. 

does severe stress restore an impaired epinephrine response?

Caparulo and Cohen thought sudden remissions of autistic behavior during blood drawing were due to “increased attentional focusing that accompanies highly arousing, emotional states.”[4] Helt et al. noted multiple reports of seemingly-mute autistic children speaking in perceiv-ed emergencies: “While these otherwise mute or almost-mute children did not produce complex, advanced speech, they did produce utterances (“look out”, “take it out”, “I don’t want to go”) that were thought to be beyond their ability.”[5] 

Intense release of epinephrine greatly accelerates brain metabolism and blood flow via beta-adrenergic receptors (BAR) of the SNS. Beta 1-adrenergic receptors increase heart rate and force of contractions, among other functions; beta 2-adrenergic receptors relax the smooth muscle of blood vessels and stimulate the sodium pump, among other functions. Epinephrine has more affinity than norepinephrine for BAR, especially beta2-AR [23]. Epinephrine from ordinary stress shifts Ca2+ and the amino acid taurine into heart muscle via BAR [82]. Intense release of epinephrine has the opposite effect. Durlach and Durlach: “[I]ntense beta-stimulation produces reverse effects on cell [taurine] influx: instead of an increase, a decrease is observed.”[83] 

Epinephrine regulates magnesium in stress and fever 

Beta-adrenergic receptors also shift magnesium ions between tissues and blood. Keenan et al. found in rats that stimulating B1AR reduced blood Mg2+; stimulating B2AR increased blood Mg2+ [84]. Most stresses shift magnesium from tissues to blood: e.g. cold, hibernation, emotional stress, shock, and anoxia [85,86]. Galland: “[T]he adrenergic effects of psychological stress induce a shift of Mg from the intracellular to the extracellular space, increasing urinary excretion and eventually depleting body stores.”[87] Durlach and Durlach concluded Mg movements into blood under stress are part of a feedback mechanism – epinephrine increases blood Mg, and high blood Mg suppresses epinephrine. 

Four endocrine glands and the amino acid taurine regulate Mg metabol-ism, they concluded. Thyroid and parathyroid hormones regulate Mg exchange between extracellular fluid and hard tissue stores in bone. Epinephrine and insulin regulate Mg exchange between extracellular fluid and soft tissue stores (e.g. liver and muscle): epinephrine moves Mg out, insulin moves Mg in. Magnesium deficiency over-stimulates release of epinephrine, inducing a paradoxical Mg deficiency with high blood Mg – or epinephrine toxicity: “Conversely, in other cases (almost 50%) the adrenal medulla response may be absent. This may result from exhaus-tion of a too prolonged reactive hypersecretion.”[83] 

Generating artificial fever in multiple sclerosis patients via injections of sterile milk, Huszák et al. detected a shift of Mg2+ from plasma into red blood cells (RBC). They suggested Mg2+ moved into cells to support the energy requirements of the enhanced metabolism of fever [88]. Magnes-ium is a cofactor for more than 300 intracellular enzymes, and essential for energy metabolism [89]. Deuster et al. detected a shift of Mg from plasma to RBC in athletes during intense exercise (treadmill) [90]. Lukaski described Deuster’s study: “[T]he greater the energy requirement from anaerobic or glycolytic metabolism, the greater the translocation of magnesium from the plasma into the red blood cells.”[91] The hyper-metabolic state of fever, however, is not anaerobic [92]. 

Magnesium/vitamin B6 for autistic disorders 

After decades collecting parents’ reports of nutritional supplements that helped their autistic child, and testing many himself, Rimland concluded that oral vitamin B6 (pyridoxine) plus magnesium gave the greatest benefit: “Adding magnesium to the B6 has repeatedly been found to be essential for best results.”[39] Rimland thought B6 was most responsible for the benefit of Mg/B6 supplements – magnesium given largely to counteract its side effects [93]. Mousain-Bosc et al., however, concluded Mg/B6 supplements also help these children by increasing intracellular Mg2+. Before taking Mg/B6, 16 of 33 ASD children had significantly lower levels of RBC Mg2+ than controls. Parents of children with low RBC Mg2+ also had low RBC Mg2+. Mg/B6 increased RBC Mg2+ levels significantly in 11 of 17 children, and improved behavior in 23 of 33. Of those who improved, however, only eight showed increased RBC Mg2+ [94]. Strambi et al. found a statistically insignificant reduction of RBC magnesium in ASD children, and a significant reduction of plasma magnesium [95]. According to Davis, persons only slightly deficient in magnesium become “irritable, high-strung, sensitive to noise, hyper-excitable, apprehensive, and belligerent.”[96] 

Magnesium is a necessary cofactor for donation of phosphate groups from ATP to the sodium pump [97]. Newman and Amarasingham proposed magnesium depletion induces “functional impairment of the ATP-dependent sodium/potassium and calcium pumps in the cell membranes and within the cell itself,” leading to calcium accumulation in vascular smooth muscle and ischemia [98]. Mauskop and Altura: “Magnesium ion plugs the NMDA [N-methyl-D-aspartate] receptor and prevents calcium ions from entering the cell. Lowering Mg2+ concentration facilitates activation of the NMDA receptor, which allows calcium to enter the cell and exert its effects both on neurons and cerebral vascular muscle.”[99] 

B6 increases intestinal absorption of Mg [100]; B6 depletion increases urinary loss of Mg [101]. B6 levels in some autistic children are high not low, however, due to impairment of the zinc-dependent enzyme pyridoxal kinase (B6-kinase), which converts pyridoxine to pyridoxal phosphate (PLP, P5P), its bioactive form. Adams et al. concluded B6 supplements may help these children by increasing intracellular levels of substrate, thus activating the defective enzyme [102]. PLP supplements may be less effective because digestion removes the phosphate group; conversion of B6 to PLP needs to happen inside the cell [103]. Conversion of B6 to PLP is also impaired when liver function is impaired [104] – a near-universal condition in children with ASD [105]. B6 metabolism is greatly inhibited by mercury, McGinnis noted: “Some specifics about autism should heighten interest in mercury. A long clinical tradition has evolved in the use of vitamin B6, and its activating enzyme (B6-kinase) is totally inhibited in the intestine at nanomolecular concentrations [of mercury] in vitro.”[106] B6-kinase also requires zinc, which mercury readily displaces from enzymes. 

Magnesium and B6 play critical roles in the biochemistry of sulfur amino acids, invariably disturbed in ASD [107]. Magnesium is required for the phosphorylation that activates sulfate; PLP is required to convert methionine to cysteine and cysteine to taurine [42]. Magnesium deficiency redistributes taurine to compensate. Durlach and Durlach: “We may presume that the Mg-deficient organism tries to aspecifically balance the membrane alteration ... by mobilization of membrane-stabilizing concentrations of TA [taurine]. But it is also conceivable that TA action on cell membranes aims at maintaining Mg in the cell.”[83] McCarty concluded intracellular taurine and extracellular magnesium each dampen neuronal hyperexcitability and counteract vasospasm [108]. 

Sodium/calcium exchange 

Under normal conditions Na enters through various leaks and also through the Na-Ca exchange and this Na is pumped out of the cell by the Na-K pump. In contrast, when the Na-K pump is inhibited, the Na leaking into the cell must be removed by the Na-Ca exchange which now acts to bring Ca in. This change of direction of the exchange is, of course, a consequence of the increased [Na+]i [intracellular Na+]. The Ca that enters the cell on the exchange must be pumped out from the cytoplasm via some energy-dependent process. In the short term this may be accomplished by intracellular sequestration of Ca2+ ions within organelles. However, if this model is to work in the steady state, then some mechanism such as a Ca-ATPase must pump Ca2+ out of the cell. Eisner 1990 [109] 

Because resting concentrations of free Ca2+ ions in the cytosol of excitable cells are minute (extracellular concentrations 20,000x greater [110]), a small increase in Ca2+ ions in cytosol greatly increases their concentration. This makes Ca2+ ions excellent signaling molecules to release neurotransmitters at synapses, secrete endocrine hormones, and contract smooth and skeletal muscles. Not all ‘signal calcium’ enters cytosol from extracellular fluid; much is stored and released by intracellular structures (organelles): the endoplasmic reticulum, sarco-plasmic reticulum, and mitochondria. Calcium signals in neurons and skeletal muscle terminate rapidly, but in smooth muscle (e.g. heart muscle) are often prolonged. Thus different tissues require different mechanisms to export and sequester free Ca2+ [111]. 

Blaustein and Lederer reviewed the physiology of sodium/calcium exchangers – intrinsic carrier proteins in the plasma membrane of virtually all animal cells [111]. Membrane calcium pumps that export Ca2+ or sequester Ca2+ in organelles are enzymes deriving their energy from ATP. Sodium/calcium exchangers are not enzymes [112], and derive their energy from ion gradients maintained by the sodium pump, and the coupling ratio (stoichiometry) of the transported ions [111]. In most cells three extracellular Na+ ions exchange for one intracellular Ca2+ ion. The direction of exchange reverses readily, depending on concentration gradients of each ion. The plasma membrane calcium pump (Ca2+-ATPase) has high affinity but low capacity for Ca2+. The sodium/calcium exchanger has low affinity but high capacity, important in tissues that expel much calcium quickly, e.g. heart muscle, where the exchanger carries virtually all Ca2+ out of cells. Sodium-calcium exchangers are most abundant in excitable tissues like the heart and brain [111]. 

When a neuron depolarizes, Ca2+ ions entering through voltage-gated channels open potassium channels to repolarize the neuron. Simons: “Intracellular Ca2+ controls the membrane permeability to K ions, and hence the overall electrical activity of most neurons.”[113] Because astrocytes do not generate action potentials, their Ca2+ signals come largely from intracellular stores, thus are slow and sustained [114]. 

Sodium entering and leaving astrocytes generates metabolic fuels 

Paemeleire reported evidence that astrocytes use sodium cotransport to take up glutamate from the synaptic space. Sodium influx activates the sodium pump, which requires glucose that astrocytes convert to lactate, a fuel neurons prefer [35]. Astrocytes also neutralize glutamate and ammonia to glutamine, an alternative fuel in brain mitochondria, especially during hypoglycemia [36]. Thus sodium entering astrocytes converts glutamate to glutamine, and sodium leaving via the sodium pump indirectly converts glucose to lactate. Lactate is an unusual molecule: by diffusing freely across cell membranes, lactate does not accumulate in cytosol, limiting production (by mass action). This allows anaerobic glycolysis (conversion of glucose to pyruvate then lactate in the absence of oxygen) to persist for minutes [23]. 

Sodium fluxes generating brain fuels appear coupled to calcium “waves” – coordinated flow of intracellular Ca2+ across the cytoplasm of many interconnected astrocytes. Charles described studies by Bernardinelli et al. [115]: “The uptake of glutamate through astrocyte glutamate trans-porters is believed to be critical to the clearance of both synaptic and extrasynaptic glutamate. Glutamate uptake may in turn activate a cascade that leads to increased glucose uptake and metabolism. Bernardinelli et al.. provide evidence that this process may occur not only in a spatially limited fashion but also as a propagated multicellular response. Using a fluorescent indicator for intracellular sodium, they showed that inter-cellular Ca2+ waves in astrocytes are associated with intercellular Na+ waves.... The authors concluded that intercellular Ca2+ waves evoked glutamate release and that Na+ waves were subsequently generated by the influx of Na+ along with glutamate through the glutamate trans-porter. They went on to show that glucose uptake occurs in the same distribution as the Na+ waves, indicating that the increase in [Na+]i evoked an increase in glucose transport.... These results suggest that propagated changes in Na+ concentration in astrocytes are a mechanism for spatially propagated activation of glucose metabolism evoked by neuronal activity.... There is growing evidence that active neurons preferentially use astrocyte-derived lactate (as opposed to glucose) as a source of metabolic energy. In the scenario proposed by Bernardinelli et al., the ultimate effect of Na+ waves is increased metabolism of glucose to lactate, which can be released and taken up by active neurons.”[116] 

TAURINE VS. INTRACELLULAR CALCIUM

In general there is a consensus that taurine is a powerful agent in regulating and reducing the intracellular calcium level in neurons. After prolonged L-glutamate stimulation, neurons lose the ability to effectively regulate intracellular calcium. This condition can lead to acute swelling and lysis of the cell, or culminate in apoptosis. Under these conditions, significant amounts of taurine (mM range) are released from the excited neuron. This extracellular taurine acts to slow the influx of calcium into the cytosol through both transmembrane ion transporters and intra-cellular storage pools. Foos & Wu (2002) [117] 

The free (nonprotein) sulfur amino acid taurine has a variety of critical functions throughout the body, notably brain osmolyte, inhibitory transmitter, and cryogen, regulator of active intracellular calcium, and magnesium complement. The value of taurine to distribute intracellular calcium safely has been most studied in the heart. Huxtable noted taurine forms a calcium salt with high affinity for heart muscle, leading to a “larger pool of bound calcium.”[118] Huxtable and Chubb concluded stress shifts Ca2+ and taurine into heart muscle via beta-adrenergic receptors of the SNS: Ca2+ to strengthen contractions, taurine to distribute the Ca2+ in organelles: “[T]his system provides a potentially important link between two agents that modulate calcium flux in the heart cell: beta-adrenergic activation stimulates both calcium and taurine influx into the heart cell, and taurine modulates the pool size of free intracellular calcium.”[82] Huxtable concluded: “Taurine and calcium function as opposing principles, both functionally and biochemically, and can be considered as a yin-yang metaphor.... Taurine is a passive agent, resisting calcium-induced changes by modifying calcium binding and antagonizing a range of calcium-dependent events, such as contrac-tility.”[119] 

Two sodium ions and one chloride ion cotransport one molecule of taurine into cells [117]. Bkaily et al. found exposing heart muscle to taurine increased intracellular Ca2+ and Na+, which they thought might be due to Na+ entering cells via the taurine-Na+ cotransporter, then exchanging for Ca2+: “Thus, the effect of taurine on [Ca]i in heart cells appears to be due to Na+ entry through the taurine-Na+ cotransporter which in turn favours transarcolemmal Ca2+ influx through the Na(+)Ca2+ \exchanger.” How does taurine help the heart by increasing intracellular Ca2+? “Taurine has the ability to increase calcium availability for contraction and at the same time protect against calcium overload injury.”[120] 

Albrecht and Schousboe noted a variety of environmental and patho-physiological insults evoke “massive release” of taurine from the CNS [121]. Release of taurine from brain is most stimulated by ischemia, free radicals, metabolic poisons, excessive glutamate, and ammonia [122]. Fever in rabbits released more taurine into CSF than heat did [32]. Taurine is also the primary osmotic suppressor of vasopressin. Sensing low ion concentrations in extracellular fluid, specialized astrocytes (pituicytes) release taurine to inhibit Ca2+ fluxes into neurons that release vasopressin. Hussy et al. concluded taurine depletion “abolishes the osmo-dependent inhibition of vasopressin release.”[123] Hypo-natremia releases taurine and glutamine from the brain to maintain cell volume [124,125]. Small organic solutes like taurine are valuable osmolytes because (unlike electrolytes) they don’t destabilize proteins or (usually) alter membrane potentials [126]. 

Despite the unquestioned value of taurine in the fetus and newborn, Nakada concluded the enormous increase in neural activity after birth requires that N-acetylaspartate (NAA) replace taurine in the brain – to buffer pH, and accelerate diffusion of high-energy phosphates from mitochondria to the neural membrane: “Taurine in fetal brain is the counterpart of NAA in adult brain. During early post-natal life, the chemical microenvironment of the neuronal cytosol undergoes conver-sion from a taurine rich environment (fetal type) to NAA profile (adult type).” Nakada found taurine inhibited diffusion of phosphocreatine (PCr), which is either “a high energy reservoir (ATP buffer) or an energy shuttle between the mitochondria and cytoplasm (PCr shuttle).”[127] The significance of this conclusion for ASD, however, is unclear, since ASD children may be taurine-deficient at an early age, brain maturation appears delayed, and taurine has many critical functions in the brain. 

taurine in autistic disorders 

Pangborn found taurine was the amino acid most wasted or depleted in urine of ASD children [42]. Taurine appears most vulnerable to abbre-viated breastfeeding [128], dietary deficiencies of precursors methionine and cysteine [129], impaired synthesis from deficiency of bioactive B6 (pyridoxal phosphate) [42], and preemptory requirements for sulfate and glutathione. Mother’s milk is rich in taurine; cow’s milk is low after calves are weaned [128]. Many mothers of autistic children breastfed one week [130]. Schultz found longer breastfeeding was associated with a decreased likelihood of developing autism [131] – yet many (but not all) infant formulas have been fortified with taurine since the 1980s [132]. The Autism Research Institute recommends 250–500mg/day of taurine for children with ASD, up to 2g/day for adults and adult-sized children [133]. 

GLUTAMINE IN AUTISTIC DISORDERS

[C]hildren in this cohort [urea cycle disorders] show other behavioral/emotional strengths, including a minimal percentage with previous diagnoses of Autism spectrum disorders, mood disorders, and other psychiatric disorders. Krivitzky et al. 2009 [134] 

Glutamine is normally the most abundant amino acid in plasma [135], yet was low in serum, plasma, and platelets of ASD children [136-140]. Because glutamine is not thought to cross the blood-brain barrier readily, the implications of low blood glutamine in these children are not recognized. Yet a sodium-dependent, concentration gradient-dependent transporter has been identified that carries glutamine from blood into astrocytes [135]. Glutamine is alternative fuel in brain neurons and astrocytes, especially during hypoglycemia [36], and primary fuel in rapidly replicating cells, e.g. blood vessel endothelial cells, intestinal mucosal cells, liver cells, and tumors [141,142]. 

Two principal intracellular enzymes regulate glutamine metabolism. Glutaminase catalyzes hydrolysis of glutamine to glutamate and ammonia; glutamine synthetase catalyzes synthesis of glutamine from glutamate and ammonia. Replicating cells tend to be avid glutamine consumers, and generally have much more glutaminase than glutamine synthetase. Skeletal muscles, brain, and lungs, which synthesize and release glutamine into blood, have more glutamine synthetase [141]. 

Astrocytes take up glutamate released at synapses and (via glutamine synthetase) neutralize it to glutamine (with no transmitter activity but much osmotic activity), which they release to neurons to reform glutamate (and GABA), and as fuel. Conversion of glutamate to glutamine requires ammonia – detoxifying both molecules. Excessive glutamine, however, causes astrocytes to swell, elevating intracranial pressure. Persons with liver damage (e.g. cirrhosis) and children with inborn urea cycle disorders (UCD) cannot detoxify all ammonia before it reaches the brain, inducing high brain ammonia and glutamine (hepatic encephal-opathy) [143]. 

Wakefield et al., however, thought brain ammonia was high in ASD but brain glutamine low, because serum glutamine was low [136] and liver dysfunction impairs glutamate transporters [37]. Distinguishing brain glutamine from glutamate by magnetic resonance spectroscopy (MRS), however, usually requires an ultra-high field. DeVito et al. detected reduced concentrations of combined glutamate/glutamine in the cortex and cerebellum of autistic boys [144]. Bernardi et al. reported reduced glutamate/glutamine in the right anterior cingulate cortex of high-functioning adults with autistic disorders [145]. Page et al., however, found glutamate/glutamine elevated in the amygdala/hippocampal region of autistic adults, and normal in the parietal region [146]. 

Conversion of glutamate to glutamine in astrocytes requires magnesium [36] and B6 [147]. The effectiveness of risperidone (Risperdal), which helped 54% of ASD persons (but aggravated 20%) [148] also suggests brain glutamine may be low. Risperidone is thought to suppress activity of serotonin and dopamine at synapses, but also stimulates glutamate uptake by astrocytes and activity of glutamine synthetase [149]. The most compelling evidence for low brain glutamine in autistic disorders, however, must be the notable lack of autistic behavior in children with high brain glutamine from urea cycle disorders [134]. 

AMMONIA IN AUTISTIC DISORDERS

Because of the harmful systemic manifestations that would otherwise result, peripheral tissues such as skeletal muscle and the brain do not release significant amounts of free ammonia into the bloodstream. Instead they have developed methods of detoxifying this compound. Both of these organs synthesize and release glutamine which transports ammonia in a nontoxic form to the intestinal tract and the kidneys. Souba 1987 [150] 

High levels of ammonia in the blood of children with autistic disorders were first detected in the early 1980s [151]. Filipek et al. found plasma ammonia significantly elevated in a majority of 100 autistic children [152]. Wakefield et al. proposed bacteria in their diseased intestines generate more ammonia than their impaired liver can clear, which reaches the brain: “Following passive diffusion across the mucosa, failure by the diseased liver to effect what should, under normal circumstances, be a high first-pass clearance, leads to excessive ammonia levels in the brain.”[37] Bradstreet et al. noted high blood ammonia is more toxic to children than adults [153]. Wang et al. recently reported high levels of fecal ammonia in ASD children [154]. 

Most ammonia is a byproduct of bacteria digesting proteins in the large intestine, and degrading glutamine in the small intestine [155]. The liver uses arginine to detoxify ammonia to urea excreted in urine [156]. The brain lacks enzymes for a complete  urea cycle, and is the organ most affected when the liver cannot clear blood ammonia at first pass (hepatic encephalopathy). Ammonia that reaches the brain is trapped by astrocytes combining ammonia and glutamate to form glutamine. Brusilow et al. concluded the primary pathology of ammonia in the brain is reversible astrocyte swelling from glutamine and its water [157]. Astrocytes combine ammonia and alpha-ketoglutarate to form glutamate. Pangborn: “Ammonia grabs alpha-ketoglutarate, especially in the ... CNS where that’s the natural ammonia detox route. Ammonia plus alpha-ketoglutarate becomes glutamate. When this occurs, taurine formation is upregulated (my observation based on whole body chem-istry).”[151] Astrocytes release taurine to compensate swelling from ammonia [158]. Albrecht and Schousboe: “[A]cute ammonia challenge appears to release taurine more readily than any other amino acid studied.”[121] 

Albrecht and Jones concluded acute ammonia toxicity releases glutamate at synapses, inducing excitation; chronic ammonia accumulation downregulates glutamate receptors and releases gamma aminobutyric acid (GABA), inducing inhibition [158]. Ammonia accumulation also shifts brain metabolism and blood flow from cortical to subcortical structures [143]. Hindfelt noted an early manifestation of hepatic encephalopathy is a “frontal lobe syndrome” (loss of executive functions) [159]. Acute high levels of blood ammonia directly impair glutamate transporters (although chronic high levels may not) [143]. Alpha-ketoglutarate is a key inter-mediate in the citric acid cycle that generates ATP [160]. 

But if high brain ammonia provokes ASD, why don’t children with urea cycle disorders show autistic behavior? Do UCD children detoxify more free ammonia than ASD children? Felipo and Butterworth noted glutamine synthetase normally functions at near-maximum capacity: “Hyperammo-nemia rapidly exceeds the brain’s capacity to synthesize glutamine, and ammonia concentrations rise significantly.”[143] If high brain ammonia doesn’t provoke autistic behavior in UCD children, why would it do so in ASD children? One obvious explanation is that ASD children are not protected by high brain glutamine. 

LOW BRAIN BLOOD FLOW IN AUTISTIC DISORDERS

Traditional fever is accompanied by ... increase in brain temperature and it should also increase brain circulation. Therefore, in situations of diminished (compromised) cerebral blood flow, fever should improve brain circulation and, thus, improve well being and performance of patients. Kiyatkin 2010 [19] 

Using computed tomography, Zilbovicius et al. detected reduced blood flow in the frontal cortex of autistic children 3-4 years old resembling blood flow in normal children half their age. Three years later, frontal perfusion was normal: “Since CBF patterns in children are related to maturational changes in brain function, these results indicate a delayed frontal maturation in childhood autism.”[161] Ohnishi et al. reported decreased regional cerebral blood flow (rCBF) in brain regions implicated in autism, and observed no region with increased rCBF [162]. Burroni et al. found global CBF significantly reduced in eleven autistic children (mean age 11.2 years), although some regions had greater than normal flow. Left hemisphere flow was less than right hemisphere flow, although both were low [163]. Degirmenci et al. detected asymmetric hypo-perfusion in various brain regions in ten autistic children (and their family members!) [164].

Meresse et al. found blood flow significantly low in the superior gyrus of the left temporal lobe: “The more severe the autistic syndrome, the more rCBF is low in this region, suggesting that left superior temporal hypoperfusion is related to autistic behavior severity.”[165] Herbert concluded recent imaging studies corroborated many previous reports of brain hypoperfusion [166]. Is low brain blood flow secondary to low brain metabolism? Friedman et al. cited reports of decreased metabolism in the “frontal lobes, basal ganglia, putamen, insula, thalamus, parietal lobes, temporal lobes, superior temporal gyri, and calcarine cortex” of ASD children [167]. 

Arginine and creatine in autistic disorders 

Another explanation for low brain blood flow is primary depletion of the amino acid arginine – required to detoxify ammonia to urea in the liver, for arginine vasopressin, and as only substrate for primary vasodilator nitric oxide. High levels of nitrite in plasma of ASD children may reflect inducible nitric oxide responding to intestinal infection [168], depleting arginine as substrate for endothelial and neuronal nitric oxide, the brain’s primary vasodilators. Carrick and Carrick reported oral arginine calms unstable emotions and improves sociability dramatically in their adult son with autism [169]. Supplemental arginine also spares glutamine. Wu et al.: “[W]hen dietary levels of arginine arehigh, intestinal synthesis of citrulline from glutamine and glutamate may be inhibited for sparing of glutamine and glutamate for other metabolic pathways.”[170] 

Arginine (with glycine) is also required to synthesize the amino acid creatine in kidneys and liver [171]. Creatine and its phosphorylated form phosphocreatine shuttle ATP from mitochondria to cytosol and the cell membrane, thus are vital for energy metabolism, especially in muscles and brain [172]. Athletes ingest many grams of creatine daily to energize muscles. 1–2 grams a day improved alertness and cognition in persons with dementia or Alzheimer’s [173]; creatine also helped persons with the CNS diseases Huntington’s and Parkinson’s [171]. 

Inborn creatine deficiencies cause mental retardation, delay acquiring speech and language, seizures, and autism [172]. Minshew et al. detected by MRS decreased levels of phosphocreatine in brains of high-functioning autistic adolescents and young men, concluding this indicated “increased utilization of [phosphocreatine] to maintain brain ATP levels, or a hypermetabolic energy state.”[174] Friedman et al. detected reduced brain creatine in 3– 4-year-old children with ASD, and reduced NAA, a marker for neuronal density and metabolism [167]. A follow-up study found less creatine and phosphocreatine in gray matter of young ASD children [175]. Hardan et al. detected by MRS reduced levels of NAA, phosphocreatine, and creatine in the left thalamus of ASD children [176]. Kleinhans et al. found no significant differences in NAA or creatine/phosphocreatine in high-functioning adults with ASD, but significant correlations between NAA and creatine and clinical ratings [177]. Wang et al. reported no significant differences in urinary creatine in ASD children compared to controls [178]. Although trials of creatine for autistic disorders have not been reported in the medical literature, Woeller reported online that oral creatine monohydrate can be very effective in ASD children with low muscle tone, low metabolic energy, poor coordination, and difficulty with expressive language [179] (see Tests and remedies). 

Creatine protects against ammonia in the developing brain, but is also reduced by ammonia, according to Braissant, who concluded that the ammonium ion (NH4+) “impairs the metabolism and transport of arginine in developing brain cells.... As arginine is precursor, among other pathways, of creatine (Cr) synthesis, NH4+ exposure of the brain can lead to disturbances in cerebral energy and in particular in its Cr content.... The main function of the Cr/PCr/CK [creatine/phosphocreatine/creatine kinase] system in vertebrate cells is the regeneration of ATP as well as the cell buffering of high energy phosphates. In CNS specifically, the importance of Cr has been shown for the dendritic and axonal elongation (growth cone migration), the Na+–K+– ATPase activity, the release of various neurotransmitters, the maintenance of membrane potential, the Ca++ homeostasis and the restoration of ion gradients. In the mammal-ian brain, total levels of Cr and CK activity are well correlated, their highest levels being reached in brain cells described with high and fluctuating energy demands.”[171] 

Are antibacterial effects of salt and fever significant? 

Herbert thought fluid/salt diets might transiently reduce intestinal bacteria [180], which cannot survive high osmolarity. Salt (like sugar) desiccates – draws water out of cells to balance osmolarity. Reports of autistic regression after a course of broad-spectrum antibiotics – usually to treat otitis media (middle ear infection) – led Sandler et al. to investigate gastrointestinal bacteria in these children. Oral vancomycin (antibiotic minimally absorbed) improved autistic symptoms impressively short-term in 11 children with regressive autism [181]. Finegold et al. subsequently found ASD children had twice as many species of intestinal bacteria as typical children, and a distinctive species (Desulfovibrio) not detected in healthy controls [182]. Adams et al. concluded: “Commonly used oral antibiotics eliminate almost all of the normal gut microbiota .... Loss of normal gut flora can result in the overgrowth of pathogenic flora, which can in turn cause constipation and other problems.”[183] Horvath and Perman reported autistic regression between 12 and 18 months was associated with the onset of gastrointestinal symptoms [184]. 

Fallon found many autistic children under the age of three with otitis media treated with the oral antibiotic amoxicillin/clavulanate (Augmen-tin), made with ammonia [185]. Analyzing medical records, Niehus and Lord concluded ASD children had more ear infections than typically developing children, treated with more antibiotics [186]. Gordon has contended for decades that the association of autism and deafness is no coincidence [187]. Greenberg et al. noted the association of acute otitis media, day care centers (DCC), antibiotic-resistant bacteria, and recommendations by the American Academy of Pediatrics and the American Academy of Family Physicians that high-dose amoxicillin/clavulanate was “the first therapeutic choice” for children in day care centers: “The development and spread of resistant organisms are facilitated in DCCs as a result of the following: (i) large numbers of children; (ii) frequent close person-to-person contact; and (iii) a wide use of antimicrobial medications. Intensive antimicrobial usage provides the selection pressure that favors the emergence of resistant organisms, while DCCs provide an ideal environment for transmission of these organisms.”[188] Ball noted Augmentin was launched in 1981 to treat “upper and lower respiratory tract infections, urinary tract infections, skin and soft tissue infections and obstetric, gynaecological and intra-abdominal infections.”[189] 

A year earlier, another pharmaceutical now implicated in ASD became popular with parents, pediatricians, and hospitals – acetaminophen (paracetamol, Tylenol), the antipyretic/analgesic of choice after aspirin was erroneously implicated in Reye’s syndrome in 1980 [190,191]. Until about 1980, about 50–60 percent of autistic children were abnormal from birth, and 40–50 percent regressed into autism at about 18 months [42]. “Around 1980,” Pangborn observed, “all this began to change. The total frequency of occurrence doubled, doubled again, and by 1995 was approximately 10 times that of 1980. Furthermore, while the onset-at-birth type had increased 3 to 4 times, the onset-at-18-months type had skyrocketed to considerably more than 10 times its 1980 level.” Pangborn concluded that most of the autistic population now appeared to have “an acquired disease caused by something that we were not doing 20 years ago.”[42] 

DISCUSSION: HOW DO FEVER AND SALT HELP?

Autism is a particularly interesting and significant clinical syndrome for neuroscience, because it is defined by abnormalities in those abilities that most distinguish humans from animals, that is, social and nonsocial behavior, language, and cognition. Minshew et al. 1993 [174] 

Parent report has confirmed reductions in adverse behaviors with fever. Despite the significance of this observation, it would be even more important if anecdotal reports of increased emotional contact and speech with fevers could be confirmed. Helt et al. 2008 [5] 

[T]he social milestones that are delayed in autism arise out of the self-regulatory milestones relative to orientation/attention, self-soothing, and the emerging ability to regulate behavior and emotions in response to social cues. Silva & Schalock 2012 [192] 

Accumulation of ammonia in brain results in a redistribution of blood flow and metabolism from cortical to sub-cortical brain regions. 
Felipo & Butterworth 2002 [143] 

Eminent researchers independently conclude children with autistic disorders lack brain energy: 

I had thought of [autistic behavior] as low energy, not enough to fire things sufficiently. Herbert 2011 [180] 

I have come to the conclusion that autism is caused by energy deficiency, the complex details being different in each child. I think the net result is that the hard wiring of the brain is held back and the child is more primitive than his chronological age. Lonsdale 2011 [193] 

Energy deficiency in the brain can arise from lack of nutrients (e.g. hypoglycemia) or oxygen, lack of blood flow to supply nutrients and oxygen, or direct impairment of energy metabolism (e.g. by enzyme deficiency). Children with autistic disorders are often hypoglycemic, brain blood flow is usually low, and a variety of metabolic deficits have been detected or suspected, notably depletion of magnesium (required for energy metabolism), amino acids, catecholamines, and detoxicants. 

Curiously, however, each child with an autistic disorder often has a relatively unique assortment (‘subset’) of metabolic deficits, although autistic behavior is distinctive and readily recognized. As Herbert put it: “How do ... so many different mechanisms induce behavior that looks the same? [180] Herbert suggested some metabolic deficits may be contributing factors. Others may be collateral damage. The simplest explanation might be that a primary metabolic deficit provokes autistic behavior – and selectively provokes secondary deficits characteristic of autistic disorders but not decisive. Energy depletion in the brain, for example, may alter mood and behavior simply by reducing metabolism in the inhibitory cortex (e.g. ‘release phenomena;’ ‘executive dysfunction’) and secondarily impair uptake of amino acids, neurotransmitters, osmolytes, and other molecules, and excretion of byproducts. Energy depletion in the cortex may explain why “human” attributes are impaired (Minshew et al.), brain maturation is delayed (Zilbovicius et al.), self-regulatory behavior is delayed (Silva & Schalock), and these children appear “more primitive” (Lonsdale). 

Cortical energy depletion may also explain why fever stimulates alertness, speech, and communication in these children, often drama-tically (Cotterill;Brown;Helt et al.). This ready reversibility led Herbert to describe autism as a dynamic encephalopathy [194] – i.e. more metabolic than structural [195]. One clue to a primary metabolic deficit comes from parents’ reports that fluid diets a day or two before medical procedures relieved autistic behavior noticeably [3]. Fluid diets to empty the gastro-intestinal tract before inspection or surgery consist of clear fluids like chicken broth, apple juice, and ginger ale, and semi-solids like gelatin and honey that leave little residue after digestion. Salt is added as a necessary nutrient, to keep the child hydrated (salt retains water), avoid diluting blood sodium/osmolarity, and make the diet more palatable [196]. Are autistic children dehydrated, so that salt and fluid help? Or is salt the decisive factor? 

Children and adolescents normally eat much more salt than adults without harm [59]. This suggests sodium turnover has value – which may explain the great salt appetite in dynamic Western societies like the U.S. and Japan. Salt cravings in ASD are a better indication of salt depletion than tightly regulated blood sodium – although salt cravings also arise from dehydration or other mineral deficiencies [51]. Eating salt elevates blood pressure for hours [6], which should help ASD children with low blood pressure from adrenal fatigue, but many have high blood pressure, at least initially. Do fluid/salt diets help only those children with fatigued/exhausted adrenals? 

Another explanation for their benefit may be that blood sodium exchanges for brain calcium. Calcium accumulation is toxic to neurons, and constricts blood vessels. Nevertheless, observations that these children lack brain energy, and the benefit of fever, invite the speculation that fluid/salt diets help primarily by accelerating brain metabolism. Blood sodium exchanging for brain calcium raises the set point, and sodium entering and leaving astrocytes generates brain fuels glutamine and lactate. 

But if fever relieves autistic behavior by accelerating brain metabolism, why do some improvements persist days after temperature returns to normal [4,18]? Does fever release a protective factor that lingers, or suppress a harmful factor that returns? One such harmful factor might be ammonia, since fever reduces appetite (anorexia) thus (presumably) ingestion of protein. Fluid/salt diets are deliberately low in protein. Despite the compelling simplicity of this explanation, fever increases blood ammonia because proteins break down faster at high temperature [197]. 

Furthermore, children with high brain ammonia from urea cycle disorders rarely show autistic behavior. This is surely a ‘smoking gun’ – but what does it imply? If high brain ammonia doesn’t provoke autistic behavior in UCD children, why would it do so in ASD children? In light of evidence of low blood and brain glutamine in ASD, the most obvious explanation is that high brain glutamine in UCD children protects against autistic behavior. 

Ammonia impairs arginine and creatine metabolism, thus high-energy phosphates. Ammonia also depletes alpha-ketoglutarate, a critical metabolite in the citric acid cycle. Ammonia induces excitability, clouding of consciousness, and a frontal-lobe syndrome with loss of cortical regulation. Ammonia accumulation shifts brain metabolism/blood flow from cortical to subcortical structures. 

Why doesn’t more brain ammonia become glutamine in ASD children? Wakefield noted liver dysfunction impairs glutamate transporters [37]. Ammonia itself acutely reduces astrocyte glutamate transporters [143]. Low blood sodium and impairment of the sodium pump impair glutamate uptake [34]. Several known deficits in ASD impair the sodium pump, notably depletion of magnesium, creatine, and ATP, hypoglycemia, and low brain blood flow. A recent study of biomarkers in ASD children by Adams et al. reported: “The autism group had much lower levels of ATP and of ... precursors to ATP” – which might also explain sulfate and methylation deficiencies, they pointed out: “ATP is required in the kidney to resorb sulphate (recycling of sulphate is important because sulphate is poorly absorbed from the gut, and conversion from cysteine is slow). This study found a significant correlation of ATP with free and total plasma sulphate ... suggesting that decreased ATP is a significant contributor to decreased sulphate levels in children with autism.”[147] Do fever and fluid/salt diets carry enough glutamate into astrocytes to detoxify ammonia and generate glutamine? More decisive may be the glutamine that skeletal muscles release as provisional fuel during the ‘fasting’ of fever and fluid/salt diets. 

But if the sodium pump is impaired in ASD, why was its protein high in the brain? Did impairment of function induce compensatory overexpres-sion of protein? Was the sodium pump overactive to remove sodium brought in by the sodium/calcium exchanger to remove calcium? The converse may be more accurate: the exchanger may be compensating impairment of the pump. Stress too shifts sodium into excitable cells (via epinephrine), activating the sodium pump. But then why does stress usually aggravate autistic behavior? One explanation may be that stress further suppresses the prefrontal cortex (PFC), aggravating release of behavior. Arnsten: “[H]igh levels of catecholamine release during stress can rapidly take PFC offline in response to danger, to switch control of behavior to more primitive brain regions ... that mediate instinctive reactions.”[45] 

Wakefield suspected intestinal bacteria in ASD children generated more ammonia than their impaired liver could clear. This might happen if an oral antibiotic given for an infection killed useful intestinal bacteria, allowing colonization by harmful (ammonia-producing) bacteria. Ammo-nia in the developing brain damages neurons, and impairs transport of arginine – required to synthesize creatine, and as substrate for nitric oxide. Acute ammonia toxicity stimulates release of glutamate at brain synapses, yet impairs its uptake by astrocytes. Blaylock argued that “excitotoxicity” from excessive glutamate (and aspartate) in food provokes autistic behavior [38]. Yasko’s clinical observations corroborate Blaylock’s view [198]. When baby food manufacturers stopped adding crystalline monosodium glutamate (MSG) directly about 1970 (!), Olney pointed out, they began adding excitatory amino acids in the form of hydrolyzed vegetable protein [199] – until negative publicity in the late 70s compelled them to stop [200]. Glutamate is not thought to cross the BBB, yet has induced brain lesions in primates [201]. 

Hoernlein noted that vaccines – especially measles, mumps, rubella (MMR) – contain hydrolyzed gelatin, a source of glutamate to preserve the viruses: “[T]he MMR vaccine ... contains 10% free glutamic acid.”[202] She quoted Benarroch: “There is a low-affinity glutamate transporter that acts as a 1:1 cystine-glutamate exchanger and carries cystine to the interior of the cell in exchange for intracellular glutamate.... Accumulation of extracellular glutamate inhibits the cystine-glutamate exchanger, resulting in depletion of cell stores of cystine.”[203] Cystine (two linked cysteine molecules) is a major precursor of other sulfur amino acids. 

Sodium depletion may begin with mothers-to-be who fear salt will increase their weight or blood pressure. Myers and Veale: “[T]he ratio between the ionic constituents [sodium/calcium] in extracellular fluid is established prenatally.”[12] Stress wastes magnesium in urine, and when adrenal aldosterone is depleted, wastes sodium as well. Because plasma sodium is closely regulated, salt depletion may be most obvious in mood and appetite [204] – especially salt appetite [51]. Sugar cravings may arise because sodium uptake in the intestines requires glucose (basis of oral rehydration therapy) – but may also reveal how desperately these children need brain fuel. 

In summary (see Table 1 and Fig.1), the benefit of fever and fluid/salt diets in autistic disorders may best be explained if the primary deficit is insufficient metabolism/blood flow in the cerebral cortex, compromising ‘human’ functions like awareness, speech, communication, and impulse control. Cortical energy metabolism is impaired by lack of nutrients and fuels: magnesium to split ATP and (with B6) help detoxify glutamate and ammonia to glutamine; glutamine to fuel intestines, muscles, and brain; arginine to detoxify blood ammonia and form nitric oxide and creatine; creatine to transport and regenerate ATP and help detoxify brain ammonia; sodium to exchange for calcium, generate energy gradients, take up glutamate into astrocytes for neutralization to glutamine, and convert glucose to lactate via the sodium pump. Cortical blood flow is impaired by arginine and magnesium depletion, ammonia and calcium accumulation, excessive vasopressin, and reduced metabolism. Intestinal bacterial colonies induced by oral antibiotics may generate more ammonia than the impaired liver can clear, which astrocytes detoxify via glutamate and alpha-ketoglutarate. 

Glutamate uptake is impaired by liver dysfunction, high blood ammonia, salt depletion, and impairment of the sodium pump. Ammonia and extracellular glutamate accumulate (hyperactivity and sedation), intracellular glutamine is depleted, brain metabolism and blood flow shift from cortex to subcortex, a frontal lobe syndrome emerges. Loss of sodium gradients secondarily impairs transport of nutrients, osmolytes, neurotransmitters, and byproducts; impairment of the sodium pump requires the sodium/calcium exchanger to remove sodium, accumulating calcium. Another pathogenic scenario implicates glutamate in vaccines; stacked vaccines may overwhelm a child’s ability to neutralize glutamate rapidly. Sodium depletion may begin with maternal deficiency, become chronic with adrenal fatigue from stress. Fever accelerates brain metabolism/blood flow by exchanging CSF sodium for brain calcium (raising the set point and activating the sodium pump, indirectly converting glucose to lactate), and releasing epinephrine and its fuels. Sodium also carries glutamate into astrocytes for neutralization to glutamine, another critical brain fuel. Fluid/salt diets raise the set point by exchanging blood sodium for brain calcium, activate the sodium pump (glucose to lactate), and neutralize glutamate and ammonia to glutamine. Because children with high brain glutamine rarely show autistic behavior, however the most compelling – and promising – explanation for the benefit of fever and fluid/salt diets may be that fasting releases glutamine from muscles as provisional fuel. 

Table 1. Best evidence 

1. Fever often relieves autistic behavior dramatically [4,9-11,15,16] 
2. Fluid/salt diets relieve autistic behavior noticeably [3] 
3. CSF sodium (fever) and blood sodium (fluid/salt diet) exchanging for brain calcium elevate the temperature set point [12,49,50]. Sodium also carries glutamate into astrocytes for neutralization to glutamine, and stimulates the sodium pump, converting glucose to lactate (which neurons prefer) [35] 
4. Salt cravings are common in ASD, blood sodium usually normal. Salt appetite is the first response to salt depletion (but may signify dehydra-tion or other mineral deficiencies) [51] 
5. The sodium pump appears impaired in ASD, to judge from conse-quences of impairment (reduced uptake of glutamate, swollen astrocytes, calcium accumulation [34]), and deficits that impair the pump: depletion of magnesium, creatine, and ATP, hypoglycemia, and low brain blood flow [94,147,156,171] 
6. Brain blood flow is consistently low in ASD [156]; brain maturation appears delayed [151]; brain energy appears low [180,193]. Autistic behavior looks “primitive” [193], and self-regulation is delayed [192] – as if the inhibitory cerebral cortex is immature or suppressed 
7. Factors detected or suspected in ASD that impair brain energy metabolism include depletion of magnesium [94], creatine [171], ATP [147], impaired conversion of glutamate to glutamine [37], which requires Mg and B6 [36,147], and depletion of alpha-ketoglutarate by ammonia [160] 
8. Factors detected or suspected that impair brain blood flow include arginine and magnesium depletion [94,159], accumulation of calcium [13] and ammonia [143], excessive release of vasopressin [53], and reduced metabolism [167] 
9. Broad-spectrum oral antibiotics inducing colonization by ammonia-producing bacteria may explain autistic regression and the epidemic [42,181-189] Vaccines, especially the MMR, contain glutamic acid (i.e. glutamate) to preserve the viruses [202] 
10. Children with high brain glutamine from urea cycle disorders are rarely diagnosed with autistic disorders [134]. ASD children have low blood and brain glutamine [136-140,144,145] 
11. The ‘fasting’ of fever and fluid/salt diets releases glutamine from muscles as fuel [49,50] 

The frequent dramatic ability of fever to elicit almost normal behavior in children with autistic disorders reveals autism is more chronic and dynamic than structural (Herbert). Emergence of cerebral cortical attributes and self-regulation during fever must imply these functions are not absent nor necessarily immature, only persistently compromised or suppressed. Reports of fever’s benefit describe emergence of aware-ness, speech, and communication – attributes of highly evolved cortical regions. Fever suppressing irritability, hyperactivity, inappropriate speech, and repetitive acts is also reported – suggesting these behaviors are ‘released’ by impaired cortical regulation. 

Fever’s most salient aspect is a profound increase in brain temperature, metabolism, and blood flow, especially in children – much greater than the hypothalamus normally allows, even in distress. Fever accelerates brain metabolism via epinephrine and its fuels, and by shifting sodium from CSF to brain – displacing calcium (raising the set point), carrying glutamate into astrocytes for neutralization to glutamine (detoxifying glutamate and ammonia), and activating the sodium pump, indirectly converting glucose to lactate. Fluid/salt diets accelerate brain metabolism by exchanging blood sodium for brain calcium (raising the set point), neutralizing glutamate and ammonia to glutamine, and activating the sodium pump (glucose to lactate). Because children with high brain glutamine rarely show autistic behavior, do fever and fluid/salt diets help primarily because fasting releases glutamine from voluntary muscles into blood as provisional fuel? 

EVALUATING THE HYPOTHESIS

Relief of autistic behavior by fluid/salt diets is presently anecdotal. Relief by fever is established, although high fevers did not help significantly more than low fevers in the sole controlled study, nor were any dramatic improvements reported [14]. A subset of persons with ASD and mito-chondrial disease regress from fever [205] – which argues those who improve from fever do not have mitochondrial disease. Despite evidence the sodium pump is overactive [13], more evidence argues the pump is impaired [34]. 

If fever accelerates metabolism via epinephrine, yet epinephrine is already high from stress, how does fever help? First, stress elevates brain temperature only about 1.0°–1.5°C [19]. Second, the acute epinephrine response is often impaired in ASD. Third, the hypothalamus produces its own epinephrine, presumably during fever. 

Although bacterial colonization after oral antibiotics readily explains the chronology of autistic regression and the epidemic, how intestinal bacteria might compromise brain metabolism is less obvious. One explanation is that ammonia in the developing brain impairs arginine transport and creatine synthesis [171]. Another is that ammonia depletes alpha-ketoglutarate needed to form ATP [151,160] Ammonia accumu-lation shifts brain metabolism/blood flow from cortical to subcortical structures [143]. High blood ammonia acutely impairs astrocyte gluta-mate transporters, reducing synthesis of glutamine [143]. Although salt cravings need not signify pathology, relief of behavior by fluid/salt diets must be a critical clue.  

Because calcium accumulation is toxic to neurons and constricts blood vessels, sodium displacing intracellular calcium from the brain might explain how fever and salt help. Possibly supporting this view is evidence that a skin patch (homeopathic dose) of reserpine (Respen-A) improves core autistic deficits significantly. Reserpine (from the rauwolfia plant), long used to reduce blood pressure, appears to deplete catecholamines from sympathetic nerve endings and the adrenal medulla,  diminishing catecholamine release during sympathoadrenal activation [206]. Reser-pine also blocks voltage-gated channels that allow calcium into cells [207]. 

Respen-A is thought to stimulate monoamine oxidase (MAO), which inactivates serotonin and norepinephrine, on the theory their excess provokes autistic behavior [208]. On the other hand, Respen-A also reduces blood calcium greatly, apparently shifting it into bones and urine. Respen-A consequently requires 2g/day of supplemental calcium to compensate [209]. Giving these children 2g of calcium/ day, especially as the antacid calcium carbonate, is controversial, Woeller acknowledged [210]. On the other hand, if Respen-A depletes intracellular calcium, Ji et al. may be accurate about its role in autistic behavior [13]. Improvements in socialization, awareness, mood, and deliberate speech from Respen-A [210] sound like relief by fever, if not as dramatic. 

TESTS AND REMEDIES

Sodium depletion may be revealed by salt cravings, concentrated urine, fractional urinary excretion, and sodium/potassium in hair. Magnesium depletion is detectable in red blood cells, although depletion of intracellular nutrients is usually best identified by the response to supplements. Taurine, glutamate, glutamine, arginine, and creatine can be measured in plasma, platelets, and urine, and in brain by MRS. Ammonia is detectable via glutamine, or orotic acid in urine [143,211]. 

Rimland recommended 8mg vitamin B6 per pound of body weight daily plus 4mg magnesium/lb. [39]. Good sources of sulfur are magnesium sulfate (Epsom salts) baths, cabbage and onions, dried fruit [107], whey protein, and magnesium taurate [108]. Taurine does not require balancing by other amino acids; no adverse effects have been reported in humans taking 6g/day [212]; excess taurine is readily excreted in urine [213]. The ARI recommends 250–500 mg/day of taurine for ASD children, up to 2g/day for adults and adult-sized children [133]. Arginine supplements stimulate blood flow even when blood levels appear normal (arginine paradox); watermelon is high in arginine and its precursor citrulline [214]. Four grams of arginine throughout the day had dramatic effects in one autistic man [169]. Zinc is another critical nutrient, especially in children afflicted by mercury, because needed to activate B6. Low-protein diets are usually recommended when ammonia is high, but Stevens et al. reported protein deficiency in rats preserved ammonia to form amino acids, whereas a high-protein diet improved tolerance to ammonia: “[W]e suggest that malnourished children may be more than normally vulnerable to the hyperammonemic syndrome.”[215] Pangborn found that buffered alpha-ketoglutarate supplements (and taurine) help ASD children detoxify ammonia [170]. Vitamin B6 protects cortical neurons from glutamate [216], as does ibuprofen (Advil) [217]. 

Creatine is highest in animal protein, especially pork and tuna, also beef, chicken, fish, and soybeans. Used by athletes to energize muscles, 1–2g/day improved alertness and cognition in persons with dementia or Alzheimer’s [164]. Woeller recommends 500mg creatine monohydrate 2x/day to begin for ASD children 3–6 years old, then 1000mg (1g) 2x/day, then an average maintenance dose of 1.5–3g/day; he has given these children 5–10g/day without adverse effects [179]. Creatine must be buffered with plenty of fluids to flush the kidneys and protect the liver. Personal experience indicates oral creatine monohydrate energizes the brain remarkably, yet calms anxiety. Taurine also calms – and greatly stimulates speech. Glutamine calms and energizes. 

Another remedy may be inulin (source of fructose) and oligosaccharides (short sugar polymers) to replace harmful intestinal bacteria with useful bacteria; lactobacillus strains may be added. Veereman explained: “In the gastrointestinal (GI) system of breast-fed babies, Bifidobacteria are soon selected and become predominant. This situation remains until wean-ing.... Human milk stimulates the growth of Bifidobacteria because of a high oligosaccharide (10–12 g/L) content.... They inspired the addition of non digestible oligosaccharides and inulin to infant food to obtain a comparable bifidogenic effect. The aim of a bifidogenic effect on the infant’s intestinal flora is to counteract the current rise of allergic diseases and to protect from GI infections.”[218] 

Salt cravings and depletion may best be treated with oral rehydration salts (ORS), isotonic mixtures of sodium/potassium salts and glucose used to rehydrate children with diarrheal diseases, also athletes and sportsmen [219]. Bardhan recommended adding glutamine to ORS: 
“[G]lutamine is able to promote the absorption of sodium and water, even more effectively than glucose.”[220] Although tumors consume gluta-mine avidly, glutamine supplements do not stimulate their growth [141]. Because glutamine degrades to ammonia in the small intestine, however, glutamine supplements must be given cautiously. Arginine and citrulline spare glutamine, and Mg/B6 are cofactors for conversion of glutamate to glutamine [36,147]. Exercise accelerates detoxification of ammonia by skeletal muscles [221]. Increased blood pressure from salt may help children with adrenal fatigue and low blood pressure; children with high blood pressure should be given salt ... with a grain of salt. 

acknowledgments 

I’m most grateful to James Harduvel of the Deschutes County Library in Bend, Oregon for resourceful retrieval of the literature; Martha Herbert (MGH), who inspired this study; Eugene Kiyatkin (NIH) and Joachim Roth (JLU), for clarifying fever; Jon Pangborn (ARI), for clues to ammonia; Fred Previc (SRI), for invaluable discussions; Stephanie Seneff (MIT) and Laurie Lenz-Marino (Mt. Holyoke), for biochemical expertise/citations; and Helen Emily Couch (in memoriam) for everything else. Special thanks to Jeff Bhavnanie of flowchart.com. 

Peter Good 
Autism Studies 
LaPine, OR 97739 
www.autismstudies.info 
autismstudies1@gmail.com 

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